Since the advent of DDT more than 50 years ago, broad-spectrum neurotoxic insecticides have provided the principal means for the control of economically important insects in agriculture and public health programs. Whereas the use of synthetic insecticides initially resulted in spectacular increases in crop yields and the suppression of some important human and animal disease vectors, the development of insecticide resistance in insect pest populations and the environmental damage caused by insecticides have become widely recognized as serious drawbacks to their use. Among the most significant environmental problems associated with the manufacture and use of insecticides are 1) their direct toxicity to nontarget organisms (including humans); 2) their persistence in the biosphere where they can accumulate and cause untoward developmental and reproductive effects in higher organisms; 3) significant point-source pollution associated with their manufacture and distribution; 4) their worldwide dispersal.
Because of these problems there have been considerable government, industry, and academic efforts to develop and implement integrated pest management ("IPM") approaches employing less toxic alternatives for insect control. Such IPM strategies typically combine several pest control techniques including better controlled and reduced applications of more specific and less persistent conventional insecticides; cultural practices; development of host plant resistance; use of "biologicals" such as predatory or parasitic insects, pathogenic bacteria, and viruses, and use of insect sex pheromones.
Many insects communicate via the release of volatile chemicals known as pheromones. Sex pheromones, for example, are typically released by the female insect at appropriate times to attract males of the same species for mating. The latter phenomenon has been exploited to prevent insect mating (and consequently reduce insect populations) by releasing sufficient quantities of synthetically produced pheromone in the field to effectively impair the ability of males to find and mate with females. Pheromones have been used in this way on a commercial basis for about 15 years, and have been shown to provide effective control for numerous insect pest species, especially Lepidopteran species (moths). Among these are the pink bollworm (Pectinophora gossypiella) in cotton, codling moth (Cydia pomonella) in apples, pears, and walnuts, oriental fruit moth (Grapholitha molesta) in peaches and nectarines, tomato pinworm (Keifera lycopersicella) in tomatoes, grape berry moth (Endopiza viteana) in grapes, artichoke plum moth (Platyptilia carduidactyla) in artichokes, beet armyworm (Spodoptera exigua) in onions and other vegetables, rice stem borer (Chilo supressalis) in rice, and Mexican rice borer (Eoreuma loftini) in sugar cane.
The commercial use of pheromones to control insect pests by mating disruption has several advantages over conventional insecticides. Pheromones are: 1) nontoxic and environmentally benign; 2) specific to one target species and do not adversely affect nontarget beneficial insects, making them extremely well suited for use in IPM programs; 3) much less likely (and have never been shown) to produce resistance in the target insect; and 4) registered for use much more easily than are conventional insecticides, typically requiring 2-4 years and less than $500,000, compared to 8-10 years and over $40 million for conventional insecticides.
Despite the many advantages pheromones exhibit over insecticides, their market penetration has been slow: the total U.S. market for pheromone-based mating disruption products was reported to be only $32 million in 1989, vs. the $6 billion worldwide annual insecticide market. The principal reason for this is that pheromones are at best only cost-competitive with insecticides. Most insect pheromones cost between $350/kg and $3,000/kg, with the pink bollworm pheromone being the most commercially advanced pheromone product on the market at $350/kg. The weekly cost of controlling pink bollworm in cotton with either pheromones or insecticides is the same: about $6-8/acre. Because more than half of the cost of pheromone products are attributable to their synthesis, and, in view of the importance of market factors governing the acceptance of pheromones for insect control, substituting less expensive enzymatically mediated steps for conventional chemical steps to reduce production cost should result in increased pheromone use.
Most insect sex pheromones are aliphatic compounds having a specific location of unsaturation and a terminal alcohol, acetate, or aldehyde functional group. These compounds are enzymatically synthesized in vivo from readily available saturated fatty acid precursors (Roelofs, et al. "Pheromone Biosynthesis in the Lepidoptera," J. Chem. Ecol. 14:2019-2031 (1988)).
In contrast to pheromone syntheses in nature, current approaches for the commercial production of pheromones employ traditional synthetic chemical routes. Because pheromones require very high purity to elicit an insect's response, these syntheses are expensive and difficult. In general, coupling reactions that use moisture- and oxygen-sensitive organometallic reagents are required to establish the correct position of the double bond. These coupling reactions require elaborate manipulations and especially pure feedstocks and solvents, and generate large amounts of organic wastes that require treatment.
Thus, the coupling reactions typically drive the cost of the process. Moreover, since pheromones are effective in such small quantities (typically a few grams per acre), the cost of pheromone production via standard techniques is unlikely to decrease significantly from volume production. It is, therefore, expected that the costs of chemical starting materials and intermediates will remain high, as is typically the case in the specialty chemicals industry, unless these high value intermediates can be formed directly from inexpensive starting materials.
For these and other reasons, there remains a need for a method for forming high value pheromone intermediates from inexpensive starting materials.